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Received for publication September 26, 2005.
Revised January 25, 2006.
Accepted for publication January 30, 2006.
and co-activators, and suppression of SHP gene Expression
Bile acids and drugs activate PXR to induce CYP3A4, which is the predominant cytochrome P450 enzymes expressed in the liver and intestine and plays a critical role in detoxifying bile acids and drugs, and protecting against cholestasis. The aim of this study is to investigate the molecular mechanism of PXR cross talk with other nuclear receptors and co-activators in regulating human CYP3A4 gene transcription. Rifampicin dose-dependently induced the CYP3A4 but inhibited small heterodimer partner (SHP) mRNA expression levels in primary human hepatocytes. Rifampicin strongly stimulated PXR and HNF4
interaction, and CYP3A4 reporter activity, which was further stimulated by PGC-1 and SRC-1 but inhibited by SHP. Mutation of the putative HNF4 binding site in the distal xenobiotic responsive element module (dXREM) did not affect CYP3A4 basal promoter activity and synergistic stimulation by PXR and HNF4. Chromatin immunoprecipitation assays revealed that rifampicin-activated PXR recruited HNF4 and SRC-1 to the CYP3A4 chromatin. On the other hand, SHP reduced PXR recruitment of HNF4 and SRC-1 to the CYP3A4 chromatin. The human SHP promoter was stimulated by HNF4? and PGC-1. Upon activation by rifampicin, PXR inhibited SHP promoter activity. Results suggest that PXR strongly induces CYP3A4 gene transcription by interacting with HNF4, SRC-1 and PGC-1. PXR concomitantly inhibits SHP gene transcription and maximizes the PXR induction of the CYP3A4 gene in human livers. Drugs targeted to PXR may be developed for treating cholestatic liver diseases induced by bile acids and drugs.
Key words:
CYP gene regulation, CYP3A, cytochrome P450 regulation, gene regulation, hepatocytes, human CYP enzymes, nuclear receptors, protein-protein interactions, PXR, transcriptional regulation
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